The long range goals of this proposal are to identify CNS sites, neurotransmitter pathways and receptor subtypes that are involved in regulating alcohol drinking behavior. Since there is convincing evidence for a genetic predisposition for high alcohol consumption among certain individuals, it would be important to determine if there exist innate neurobiological abnormalities which underlie this vulnerability to alcohol abuse. An "Alcohol Reward Circuit" (ARC) is proposed which mediates the reinforcing properties of ethanol and regulates alcohol drinking. Innate abnormalities within the ARC are postulated to be underlying neurobiological factors which enhance athe rewarding effects of ethanol and promote high alcohol-drinking behavior in individuals vulnerable to alcohol addiction. This hypothesis will be tested using the selectively bred alcohol-preferring P and high alcohol drinking HAD lines and their counterparts, the alcohol-nonpreferring NP and low alcohol drinking lAD rats, the using the F2 generation of high and low alcohol drinkers obtained by intercrossing P and P rats. Using HPLC-EC techniques, the contents of serotonin (5-HT) and dopamine (DA_) will be determined in regions of the ARC of male, alcohol-naive P and NP rats, high and low F2 animals, and alcohol-naive HAD and lAD replicate lines. Quantitative autoradiography procedures will be used to determine the regional and subregional densities of certain subtypes of receptors in the CNS of the selectively bred and F2 rats. For comparative purposes, the contents of DA and 5-HT, and the densities of certain receptor subtypes will be determined in the CNS of unselected Wistar rats and the N/Nih heterogeneous stock rats. Quantitative autoradiography following the I.v. administration of [14C]2- deoxyglucose will be used to study the effects of oral self-administration and intragastric administration of ethanol on local cerebral glucose utilization rates int he CNS of selectively bred rats. In vivo microdialysis procedures will be used to examine autoregulation, as well as GABA nd 5-HT regulation, of the ventral tegmental area DA system of the high and low alcohol-seeking rats. The effects of oral self-administration and intragastric administration of ethanol on extracellular levels of DA and 5-HT in the nucleus accumbens of selectively bred rats will also be determined. The overall results of this proposal will establish if there are innate differences int he proposed ARC between disparate alcohol drinking groups and if the response of this system is more sensitive tot he rewarding actions of ethanol int he high alcohol drinking rats. Such findings would help establish the CNS sites, neuronal pathways and receptor subtypes which might be involved in regulating alcohol drinking behavior. This knowledge could aid in the development of novel pharmacological therapies for the treatment of alcoholism.